Abstracts

Rationale: Despite numerous therapies for epilepsy, over 30% of patients remain resistant to available antiseizure drugs (ASDs). However, the processes that contribute to pharmacoresistant epilepsy are unclear. We have previously demonstrated that administration of the ASD, lamotrigine (LTG), which preferentially inhibits the fast-inactivation state of sodium channels, during the corneal kindling process can also promote resistance to other ASDs that preferentially block the fast-inactivated state of sodium channels (e.g. carbamazepine). Further, LTG-resistant corneal kindled mice (CKM) were also resistant to valproic acid and retigabine (Koneval, Knox et al. 2018). However, it is unknown the extent to which inhibition of slow inactivation state of sodium channels leads to pharmacoresistance. Therefore, we sought to determine whether chronic administration of lacosamide (LCM), which preferentially inhibits the slow inactivation state of sodium channels, during the corneal kindling process would induce a pharmacoresistant CKM.

Methods: Male CF-1 mice (n=40/group; 18-25 g at kindling start, Envigo) were administered an anticonvulsant dose of lacosamide (LCM; 4.5 mg/kg, ip), lamotrigine (LTG; 8.5 mg/kg, ip), or vehicle (VEH; 0.5% methylcellulose) 0.5-1 hour prior to each twice daily corneal kindling session for two weeks until mice achieved criterion of five consecutive Racine stage 5 seizures, consistent with our LTG-resistant CKM methods. A subset of mice (n=10/group) were euthanized 48 hours after acquisition of the fully kindled state for immunohistochemistry. Subsequent evaluations of the dose-related antiseizure efficacy of mechanistically distinct ASDs, LTG, LCM, carbamazepine, levetiracetam, gabapentin, perampanel, valproic acid, phenobarbital, and topiramate was then performed in the remaining fully kindled mice. The extent of astrogliosis in LCM-, LTG-, and VEH-kindled mice was then assessed by immunohistochemistry.

Results: Neither LCM nor LTG administration affected the number of mice that achieved kindling criterion: VEH (29/39 mice); LTG (33/40 mice); LCM (31/40 mice). Mice treated with either LCM or LTG during the kindling process were highly resistant to LCM, LTG, and carbamazepine. There was a reduction in sensitivity to perampanel, valproic acid, and phenobarbital in the LTG- and LCM-kindled mice. However, levetiracetam and gabapentin both reduced the kindled seizure in LCM- and LTG-kindled mice to the same degree as VEH-kindled mice. Topiramate was not effective in any kindled mouse cohort at the maximum doses tested (20 mg/kg). The extent of astrogliosis and exploratory behavior in an open field will be further discussed.

Conclusions: This study suggests that early, chronic administration of sodium channel blocking ASDs, regardless of inactivation state preference, significantly influences the development of pharmacoresistance in the corneal kindled mouse model. This study carries significant implications for the selection of early ASD monotherapy in newly diagnosed epilepsy.

Funding: Please list any funding that was received in support of this abstract.: This study was supported by the University of Washington Department of Pharmacy.